DE1668685B2 - 17-hydroxy- and 17-acyloxy-6beta, 7 beta-epoxy-1 alpha, 2 alpha-methylene-4-pregnen-3,20-diones, processes for their preparation and agents containing them - Google Patents
17-hydroxy- and 17-acyloxy-6beta, 7 beta-epoxy-1 alpha, 2 alpha-methylene-4-pregnen-3,20-diones, processes for their preparation and agents containing themInfo
- Publication number
- DE1668685B2 DE1668685B2 DE19681668685 DE1668685A DE1668685B2 DE 1668685 B2 DE1668685 B2 DE 1668685B2 DE 19681668685 DE19681668685 DE 19681668685 DE 1668685 A DE1668685 A DE 1668685A DE 1668685 B2 DE1668685 B2 DE 1668685B2
- Authority
- DE
- Germany
- Prior art keywords
- methylene
- pregnen
- dione
- epoxy
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 239000004593 Epoxy Substances 0.000 claims description 11
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Chemical group 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002280 anti-androgenic effect Effects 0.000 description 3
- 231100000546 inhibition of ovulation Toxicity 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- -1 potassium carbonate Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 201000000736 Amenorrhea Diseases 0.000 description 2
- 206010001928 Amenorrhoea Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 231100000540 amenorrhea Toxicity 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000003152 gestagenic effect Effects 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- QMBJSIBWORFWQT-UHFFFAOYSA-N (17-acetyl-6-chloro-10,13-dimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthren-17-yl) acetate Chemical compound C1=C(Cl)C2=CC(=O)CCC2(C)C2C1C1CCC(C(C)=O)(OC(=O)C)C1(C)CC2 QMBJSIBWORFWQT-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- VRDBIJCCXDEZJN-UHFFFAOYSA-N 2-piperidin-1-ylacetic acid Chemical compound OC(=O)CN1CCCCC1 VRDBIJCCXDEZJN-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 206010063146 Uterine hypoplasia Diseases 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 208000030270 breast disease Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000004246 corpus luteum Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
CHa CH a
worin R Wasserstoff oder eine Acylgruppe, X Chlor oder Brom und Ac eine Acylgruppe bedeutet, in einem gegen die Reaktionspartner inerten Lösungsmittel mit Basen umsetzt und gegebenenfalls eine freie 17-Hydroxygruppe verestert.where R is hydrogen or an acyl group, X is chlorine or bromine and Ac is an acyl group, in reacts a solvent inert to the reactants with bases and optionally a free 17-hydroxy group esterified.
Die Erfindung betrifft neue 17-Hydroxy- undThe invention relates to new 17-hydroxy and
17 ■ Acyloxy - 6/3,7/3 - epoxy ■ 1α,2<χ - methylen - 4 - pre-17 ■ acyloxy - 6 / 3.7 / 3 - epoxy ■ 1α, 2 <χ - methylene - 4 - pre-
gnen-3,20-dione, in denen die Acyloxygruppe bis zu 15 Kohlenstoff atome enthält oder sich von einer an-gnen-3,20-diones, in which the acyloxy group contains up to 15 carbon atoms or differs from another
5 organischen Säure ableitet.5 organic acid derived.
Die Säurereste leiten sich von SäurHi mit bis zu 15 Kohlenstoffatomen, die in der '* Steroidchemie üblicherweise für Veresterungen angewandt werden, ab. Diese Carbonsäuren können auch ungesättigt,The acid residues derive from acid Hi with up to 15 carbon atoms used in '* steroid chemistry usually used for esterifications. These carboxylic acids can also be unsaturated,
ίο verzweigt, mehrbasisch oder in üblicher Weise, z. B. durch Hydroxyl-, Amino-, Oxogruppen oder Halogenatome, substituiert sein. Geeignet sind auch cycloaliphatische, aromatische, gemischt aromatisch-aliphatische oder heterocyclische Säuren, die ebenfalls in üblicher Weise substituiert sein können. Als bevorzugte Säuren zur Ausbildung des Acylrestes seien beispielsweise genannt: Essigsäure, Propionsäure, Capronsäure, Önanthsäure, Undecylsäure, Ölsäure, Trimethylessigsäure, Halogenessigsäure, Dichloressig-ίο branched, polybasic or in the usual way, e.g. B. be substituted by hydroxyl, amino, oxo groups or halogen atoms. Cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which are also used in Can be substituted in the usual way. Preferred acids for forming the acyl radical are, for example called: acetic acid, propionic acid, caproic acid, enanthic acid, undecylic acid, oleic acid, trimethylacetic acid, Haloacetic acid, dichloroacetic acid
ao säure, Cyclopentylpropionsäure, Phenylpropionsäure, Phenylessigsäure, Phenoxyessigsäure, Dialkylaminoessigsäure, Piperidinoessigsäure, Bernsteinsäure, Benzoesäure u. a. Für die Herstellung wasserlöslicher Präparate kommen insbesondere Ester anorganischer Säuren in Betracht, wie die der Schwefel- und der Phosphorsäure.ao acid, cyclopentylpropionic acid, phenylpropionic acid, Phenylacetic acid, phenoxyacetic acid, dialkylaminoacetic acid, piperidinoacetic acid, succinic acid, benzoic acid and others. For making water soluble Preparations come into consideration in particular esters of inorganic acids, such as those of the sulfuric and the Phosphoric acid.
Die neuen 6j8,7/3-Epoxy-la,2a-methylensteroide besitzen wertvolle pharmakologische Eigenschaften. Sie zeigen eine überraschend gestagene Wirksamkeit, besonders nach oraler Verabfolgung. Ein besonderer Vorteil der ernndungsgemäßen Verbindungen liegt darin, daß diese praktisch keine antiandrogene Nebenwirkung besitzen. Überraschenderweise entfalten die neuen Gestagene auch in hohen Dosen keine zentrale Hemmwirkung (Ovulationshemmung).The new 6j8,7 / 3-epoxy-la, 2a-methylensteroide possess valuable pharmacological properties. They show surprisingly gestagenic effectiveness, especially after oral administration. A particular advantage of the connections according to the invention lies in that they have practically no antiandrogenic side effects. Surprisingly, the New gestagens do not have a central inhibitory effect even in high doses (inhibition of ovulation).
Die folgende Tabelle zeigt die Überlegenheit der ernndungsgemäßen Verbindungen am Beispiel des 17 - Acetoxy - 6/3,7/3 - epoxy - 1α,2« - methylen - 4 - pregnen-3,20-dions (I). Als Vergleichssubstanz dient das bekannte Gestagen6-Chlor-17-acetoxy-4,6-pregnadien-3,20-dion (II).The following table shows the superiority of the connections according to the designation using the example of 17 - acetoxy - 6 / 3.7 / 3 - epoxy - 1α, 2 «- methylene - 4 - pregnen-3,20-dione (I). The known gestagen 6-chloro-17-acetoxy-4,6-pregnadiene-3,20-dione is used as a comparison substance (II).
Dosispo
dose
Schwellenwertpc
Threshold
Dosis p. 0.
dose
(%)inhibition
(%)
Die gestagene Wirkung wurde im üblichen Clauberg-Test geprüft.The gestagenic effect was tested in the usual Clauberg test.
Als Schwellenwert wurde die Gesamtdosis bestimmt, die bei mindestens zwei von drei Kaninchen eine transformatorische Umwandlung des Endometriums bewirkt.The total dose was determined as the threshold value, which is one in at least two out of three rabbits transforms the endometrium.
Die Ovulationshemmung wurde durch Tubeninspektion überprüft.The ovulation inhibition was checked by tube inspection.
Zur Bestimmung der antiandrogenen Nebenwirkung erhielten kastrierte männliche Ratten über 7 Tage täglich die Testsubstanz per os (p. o.) verabreicht.To determine the antiandrogenic side effect, castrated male rats were given for 7 days the test substance administered orally (p. o.) daily.
Über den gleichen Zeitraum erhielten die Tiere täglich 0,1 mg Testosteronpropionat subcutan. Am 8. Tag wurden die Tiere getötet und die Gewichte der Geschlechtsdrüsen bestimmt. Es wurde die durch die Testsubstanz bewirkte prozentuale Hemmung des Wachstums der Samenblasen (SbI.) und der Prostata (Pr.) ermittelt.Over the same period of time, the animals received 0.1 mg testosterone propionate subcutaneously daily. On the 8th day the animals were sacrificed and the weights of the sex glands were determined. It was made by the Test substance caused a percentage inhibition of the growth of the seminal vesicles (SbI.) And the prostate (Pr.) Determined.
Das Hauptanwendungsgebiet der erfindungsgemäßen Wirkstoffe ist die Behandlung folgenderThe main field of application of the active ingredients according to the invention is the treatment of the following
3 43 4
gynäkologischer Störungen: Primäre Amenorrhoe und zweckmäßigerweise mit einem reaktionsfähigen Säuresekundäre Amenorrhoe von längerer Dauer, Zyklus- derivat in Gegenwart basischer Reagenzien durchgestörungen bei unzureichender Gelbkörperfunktion, führt. Speziell genannt seien der Umsatz mit Säure-Endometriose, Uterushypoplasie, prämenstruelle Be- anhydrid bzw. -halogenid in Gegenwart von Pyridin schwerden und Mastopathie. 5 in der Hitze.Gynecological disorders: Primary amenorrhea and expediently with a reactive acid secondary amenorrhea of longer duration, cycle derivative in the presence of basic reagents, leads to disruptions in the case of inadequate corpus luteum function. The conversion with acid endometriosis, uterine hypoplasia, premenstrual anhydride or halide in the presence of pyridine may be mentioned in particular discomfort and mastopathy. 5 in the heat.
Die Dosierung erfolgt entsprechend der Schwere des Die als Ausgangsstoffe des erfindungsgemäßen VerKrankheitsfalles. Im allgemeinen wird man zwischen fahrens dienenden, in der Literatur bisher nicht be-5 und 100 mg täglich verabfolgen. Die Herstellung der schriebenen 60-Hydroxy- bzw. 6/?-Acyloxy-7a-halogen-Arzneimittelspezialitäten erfolgt in üblicher Weise, steroide können aus den entsprechenden J'-ungeindem man die Wirkstoffe mit geeigneten Zusätzen, io sättigten Steroiden hergestellt werden. Trägersubstanzen und Geschmackskorrigentien zu den So erhält man beispielsweise aus 17-Acyloxyhandelsüblichen Applikationsformen verarbeitet. Für l«,2«-methylen-4,6-pregnadien-3,20-dion mit N-Bromdie orale Applikation kommen insbesondere Tabletten, bzw. N-Chlor-succinimid und Wasser in Gegenwart Dragees, Kapseln, Pillen, Suspensionen oder Lösungen von Perchlorsäure in Dioxan folgende 6/S-Hydroxyin Frage. 15 7«-halogensteroide:The dosage is carried out according to the severity of the die as starting materials of the disease case according to the invention. In general, 5 and 100 mg will be administered daily between those used for driving, which has not yet been found in the literature. The 60-hydroxy or 6 /? - acyloxy-7a-halogen drug specialties are produced in the usual way; steroids can be produced from the corresponding substances by using the active ingredients with suitable additives, io saturated steroids. Carrier substances and taste corrections for the So are obtained, for example, from commercially available 17-acyloxy application forms. For 1 ", 2" -methylene-4,6-pregnadiene-3,20-dione with N-bromine oral administration, especially tablets or N-chlorosuccinimide and water are used Dragees, capsules, pills, suspensions or solutions of perchloric acid in dioxane follow the 6 / S-Hydroxyin question. 15 7 «-halogen steroids:
oxy-la^Ä-methylen-^pregnenO^O-dionen, dadurch ?Ä . Brom . 6ß . h d . 17 . nexanoyloxy-oxy-la ^ Ä-methylen- ^ pregnenO ^ O-diones, thereby ? Ä . Bromine . 6ß . hd . 17th ne xanoyloxy-
gekennzeichnet, daß man 6/?-Hydroxy- bzw. 6/>-Acyl- !«,^-methylen^-pregnen-S^O-dion als Öl.characterized in that 6 /? - hydroxy or 6 /> - acyl! «, ^ - methylene ^ -pregnen-S ^ O-dione as an oil.
oxy-7a-halogensteroide der allgemeinen Formel »ο 7χ . chlor /6ß. hy$to^. 17. acetoxy. la>-me-oxy-7a-halogen steroids of the general formula »ο 7χ . chlorine / 6ß. hy $ to ^ . 17th acetoxy . la> - me -
thylen-4-pregnen-3,20-dion, F. 239 bis 239,5°C.ethylene-4-pregnen-3,20-dione, m.p. 239 to 239.5 ° C.
Aus n-Acetoxy-la^A-methylen-^o-pregnadien-3,20-dion mit N-Brom- bzw. N-Chlorsuccinimid und 35 der entsprechenden Carbonsäure in chlorwasserstoffgesättigtem Tetrahydrofuran entstehen beispielsweiseFrom n-acetoxy-la ^ A-methylen- ^ o-pregnadiene-3,20-dione with N-bromo- or N-chlorosuccinimide and 35 of the corresponding carboxylic acid in tetrahydrofuran saturated with hydrogen chloride are formed, for example
mit Essigsäure:with acetic acid:
7« - Brom - 60,17 - diacetoxy - l«,2a - methylen-30 4-pregnen-3,20-dion, F. 194 bis 195°C.7 "- bromine - 60.17 - diacetoxy - 1", 2a - methylene-30 4-pregnen-3,20-dione, m.p. 194 to 195 ° C.
7λ - Chlor - 6^,17 - diacetoxy -1<%,2« - methylen-4-pregnen-3,20-dion, F. 237 bis 238°C.7λ - chlorine - 6 ^, 17 - diacetoxy -1 <%, 2 «- methylene-4-pregnen-3,20-dione, m.p. 237 to 238 ° C.
mit Ameisensäure:with formic acid:
35 7«-Brom-6/?-formyloxy- 17-acetoxy-l<x,2«-methy-35 7 "-Brom-6 /? - formyloxy- 17-acetoxy-1 <x, 2" -methy-
worin R Wasserstoff oder eine Acylgruppe, X Chlor len-4-pregnen-3,20-dion, F. 217 bis 218,50C.wherein R is hydrogen or an acyl group, X is chlorine len-4-pregnene-3,20-dione, mp 217 to 218.5 0 C.
oder Brom und Ac eine Acylgruppe bedeutet, in einem 7«-Chlor-6/?-formyloxy-17-acetoxy-l<x,2<x-methy-or bromine and Ac is an acyl group, in a 7 "-chloro-6 /? - formyloxy-17-acetoxy-1 <x, 2 <x-methy-
gegen die Reaktionspartner inerten Lösungsmittel mit len-4-pregnen-3,20-dion, F. 247 bis 2480C.against reaction partner inert solvent with len-4-pregnene-3,20-dione, mp 247-248 0 C.
droxygruppe verestert. 40 if e 18 ρ 1 e 1 1esterified droxy group. 40 if e 18 ρ 1 e 1 1
Als inerte Lösungsmittel dienen vorzugsweise mit 10,0 g 7«-Brom-6^-hydroxy-17-acetoxy-l«,2a-me-Wasser mischbare Lösungsmittel, wie Methanol, thylen-4-pregnen-3,20-dion werden in 200 ml Äthanol Äthanol, Aceton, Tetrahydrofuran, Dimethylsulfoxid und 100 ml Aceton gelöst, mit einer Lösung von 10 g oder Gemische von diesen Lösungsmitteln, wie Kaliumcarbonat und 25 ml Wasser versetzt und Äthanol mit Aceton. 45 48 Stunden bei 25° C gerührt. Danach wird in WasserThe inert solvents used are preferably solvents which are miscible with 10.0 g of 7'-bromo-6 ^ -hydroxy-17-acetoxy-1 ', 2a-me-water, such as methanol, ethylene-4-pregnen-3,20-dione in 200 ml of ethanol Ethanol, acetone, tetrahydrofuran, dimethyl sulfoxide and 100 ml of acetone dissolved with a solution of 10 g or mixtures of these solvents, such as potassium carbonate and 25 ml of water, and Ethanol with acetone. 45 stirred at 25 ° C. for 48 hours. After that, in water
Als Basen für den erfindungsgemäßen Oxiranring- eingegossen, der Niederschlag abgesaugt, gewaschen, Schluß kommen beispielsweise Alkalimetallcarbonate getrocknet und aus Aceton/Hexan umkristallisiert, und -hydrogencarbonate, wie Kaliumcarbonat und Man erhält 7,15 g 17-Acetoxy-6jS,7/?-epoxy-l«,2a-me-Natriumhydrogencarbonat, Alkalimetallhydroxide, wie thylen-4-pregnen-3,20-dion vom Schmelzpunkt 244 bis Kalium- und Natriumhydroxid, Alkalimetallalkoho- 50 2450C. UV: E310 — 15 800. late, wie Kalium-tert.-butylat, u. a. in Frage. Das gleiche 6^,7/9-Epoxid entsteht analog ausPoured in as bases for the oxirane ring according to the invention, the precipitate is filtered off with suction, washed, and finally, for example, alkali metal carbonates are dried and recrystallized from acetone / hexane, and hydrogen carbonates, such as potassium carbonate, and 7.15 g of 17-acetoxy-6jS, 7 /? - epoxy-1 «, 2a-me-sodium hydrogen carbonate, alkali metal hydroxides, such as ethylene-4-pregnen-3,20-dione from melting point 244 to potassium and sodium hydroxide, alkali metal alcohols 50 245 0 C. UV: E 310-15 800 late such as potassium tert-butoxide, among others. The same 6 ^, 7/9 epoxy is produced analogously from
Je nach der Stärke der eingesetzten Base und der 7«-Brom-6/?,17-diacetoxy- 1λ,2λ-methylen-4-pre-Höhe der Reaktionstemperatur erhält man mehr oder gnen - 3,20 ■ dion und aus 7« - Brom - 6ß - fonnyloxyminder große Anteile an Verseifungsprodukt. Durch 17-acetoxy-la,2«-methylen-4-pregnen-3,20-dion. geeignete Wahl der Reaktionsbedingungen kann man 55 «Depending on the strength of the base used and the 7 "-Brom-6 / ?, 17-diacetoxy-1λ, 2λ-methylene-4-pre-height of the reaction temperature, more or less - 3.20 ■ dione and from 7" - Bromine - 6ß - formylloxy in large proportions of the saponification product. By 17-acetoxy-1, 2'-methylene-4-pregnen-3,20-dione. a suitable choice of reaction conditions can be found
zu freien oder zu veresterten 17«-Hydroxyverbindun- Beispiel ζ to free or to esterified 17 «-hydroxy compounds Example ζ
gen gelangen. So entsteht mit Kaliumcarbonat in Eine Lösung von 1,2 g 7«-Chlor-6yi-hydroxy-17-acet-Äthanol und Aceton bei Raumtemperatur das oxy-l«,2«-methylen-4-pregnen-3,20-dion in 241 Me-ββ,Ίβ-Ερούά mit der unveränderten Acyloxygruppe thanol wird mit 600 mg Kaliumcarbonat in 3 ml Wasser in 17a-Stellung. Mit den gleichen Reaktionsmitteln 60 versetzt und 3 Stunden zum Sieden erhitzt. Danach entsteht in der Hitze nach einer Reaktionszeit von etwa wird in Wasser gegossen, der ausgefallene Nieder-20 Stunden ein Epoxid, dessen 17-Acyloxygruppe schlag abgesaugt, in Methylenchlorid aufgenommen, weitgehend verseift ist. Mit Kaliumhydroxid als Base mit Wasser gewaschen, getrocknet und im Vakuum bildet sich bereits nach kurzer Reaktionszeit bei eingeengt. Nach Chromatographie an Kieselgel wer-Raumtcmperatur das 6jJ,7/J-Epoxid mit der freien 65 den, umkristallisiert aus Isopropyläther, 650 mg 17«-Hydroxygruppe. 17 - Acetoxy - 6ß,lß - epoxy ■ 1«,2α - methylen - 4 - pre-get gen. Thus, with potassium carbonate in a solution of 1.2 g of 7 "-chloro-6yi-hydroxy-17-acet-ethanol and acetone at room temperature, the oxy-1,2" -methylene-4-pregnen-3,20-dione is formed in 241 Me- ββ, Ίβ-Ερούά with the unchanged acyloxy group, ethanol is mixed with 600 mg of potassium carbonate in 3 ml of water in the 17a position. The same reactants 60 are added and the mixture is heated to the boil for 3 hours. Thereafter, in the heat, after a reaction time of about about 20 hours, it is poured into water, the precipitated epoxide is an epoxide, the 17-acyloxy group of which is sucked off, taken up in methylene chloride, largely saponified. Washed with potassium hydroxide as the base with water, dried and in vacuo forms after a short reaction time with concentrated. After chromatography on silica gel at room temperature, the 6jJ, 7 / J-epoxide with the free 65 denier, recrystallized from isopropyl ether, 650 mg of 17 "-hydroxy group. 17 - acetoxy - 6ß, lß - epoxy ■ 1 «, 2α - methylene - 4 - pre-
Die gewünschtenfalls nachträgliche Veresterung gnen-3,20-dion vom Schmelzpunkt 240 bis 242° C er- bzw. Reacylierung der 17«-Hydroxygruppe wird halten. UV: S240 = 15 000.If desired, subsequent esterification of 3,20-dione from a melting point of 240 to 242 ° C. or reacylation of the 17'-hydroxy group will continue. UV: S 240 = 15,000.
Das gleiche 6/?,7/?-Epoxid entsteht analog aus 7a-Chlor-6/?,17-diacetoxy-l<x,2«-methylen-4-pregnen-3,20-dion und aus 7«-Chlor-6/?-forrnyloxy-17-acetoxyla,2a-methylen-4-pregnen-3,20-dion.The same 6 / ?, 7 /? - epoxy is produced analogously 7a-chloro-6 / ?, 17-diacetoxy-1 <x, 2 "-methylene-4-pregnen-3,20-dione and from 7" -chloro-6 /? - forrnyloxy-17-acetoxyla, 2a-methylene -4-pregnen-3,20-dione.
3,0 g 7a-Brom-6/?-hydroxy-17-acetoxy-la,2<x-methylen-4-pregnen-3,20-dion werden in 60 ml Äthanol gelöst, mit einer Lösung von 1,5 g Kaliumcarbonat in 7,5 ml Wasser versetzt und 24 Stunden zum Sieden erhitzt. Danach wird in Wasser gegossen, der Niederschlag abgesaugt, gewaschen, getrocknet und aus Aceton/Hexan umkristallisiert. Man erhält 1,56 g 17 - Hydroxy - 6β,Ίβ - epoxy - 1λ,2λ - methylen - 4 - pregnen-3,20-dion vom Schmelzpunkt 280 bis 283° C. UV: εΜ0 = 15 100.3.0 g of 7a-bromo-6 /? - hydroxy-17-acetoxy-la, 2 <x -methylene-4-pregnen-3,20-dione are dissolved in 60 ml of ethanol with a solution of 1.5 g Potassium carbonate is added to 7.5 ml of water and heated to boiling for 24 hours. It is then poured into water, the precipitate is filtered off with suction, washed, dried and recrystallized from acetone / hexane. 1.56 g of 17-hydroxy- 6β, Ίβ- epoxy-1λ, 2λ-methylene-4-pregnen-3,20-dione with a melting point of 280 to 283 ° C. are obtained. UV: ε Μ0 = 15,100.
Eine Lösung von 500 mg 7«-Brom-6/J-hydroxy-17-acetoxy-l«,2*-methylen-4-pregnen-3,20-dion inA solution of 500 mg of 7 "-Brom-6 / I-hydroxy-17-acetoxy-1", 2 * -methylene-4-pregnen-3,20-dione in 10 ml Äthanol und 5 ml Aceton versetzt man mit 2,5 ml einer 20%igen wäßrigen Kalilauge und rührt 30 Minuten bei Raumtemperatur. Das Gemisch wird in Wasser eingegossen, die ausgefällte Substanz abgesaugt, mit Wasser gewaschen, im Vakuum getrocknet und aus Aceton/Hexan umkristallisiert. Man erhält 297 mg 17 - Hydroxy - 6β,Ίβ - epoxy - 1λ,2<χ - methylen-4-pregnen-3,20-dion vom Schmelzpunkt 279 bis 2810C.10 ml of ethanol and 5 ml of acetone are mixed with 2.5 ml of a 20% strength aqueous potassium hydroxide solution and stirred for 30 minutes at room temperature. The mixture is poured into water, the precipitated substance is filtered off with suction, washed with water, dried in vacuo and recrystallized from acetone / hexane. This gives 297 mg of 17 - hydroxy - 6β, Ίβ - epoxy - 1λ, 2 <χ - methylene-4-pregnene-3,20-dione of melting point 279-281 0 C.
1,0 g 7<% - Brom - 6ß - hydroxy -17 - hexanoyloxyl(X,2«-methylen-4-pregnen-3,20-dion werden unter den in Beispiel 1 beschriebenen Bedingungen umgesetzt.1.0 g of 7% bromine- 6β- hydroxy-17-hexanoyloxyl (X, 2 ”-methylene-4-pregnen-3,20-dione are reacted under the conditions described in Example 1.
is Das Rohprodukt wird an Kieselgel chromatographiert. Mit 9 bis 11% Aceton/Pentan eluiert man 550 mg 17 - Hexanoyloxy - 6ß,lß - epoxy - 1α,2« - methylen-4-pregnen-3,20-dion als zähes Öl. UV: C840 = 15 400. Das Öl erstarrt nach einiger Zeit zu einer kristallinenThe crude product is chromatographed on silica gel. With 9 to 11% acetone / pentane, 550 mg of 17-hexanoyloxy- 6β, 1β -epoxy-1α, 2 "- methylene-4-pregnen-3,20-dione are eluted as a viscous oil. UV: C 840 = 15,400. The oil solidifies to a crystalline one after some time
ao Masse, die bei 129 bis 130°C schmilzt.ao mass that melts at 129 to 130 ° C.
Claims (6)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL31038A IL31038A (en) | 1968-01-11 | 1968-11-08 | 17-hydroxy-and 17-acyloxy-6beta,7beta-epoxy-1alpha,2alpha-methylene-4-pregnene-3,20-diones and process for their manufacture |
| FI339668A FI45177C (en) | 1968-01-11 | 1968-11-28 | Process for the preparation of 17-hydroxy- and 17-acyloxy-6beta, 7beta -epoxy-1alpha, 2alpha-methylene-4pregnene-3,20-diones. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1967SC040469 DE1643017B2 (en) | 1967-03-31 | 1967-03-31 | PROCESS FOR THE PRODUCTION OF 6-CHLORO-1,2ALPHA-METHYLENE DELTA HIGH 4,6-PREGNADIENES |
| DESC041823 | 1968-01-11 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1668685A1 DE1668685A1 (en) | 1971-10-07 |
| DE1668685B2 true DE1668685B2 (en) | 1974-08-29 |
| DE1668685C3 DE1668685C3 (en) | 1975-04-24 |
Family
ID=25993457
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1967SC040469 Granted DE1643017B2 (en) | 1967-03-23 | 1967-03-31 | PROCESS FOR THE PRODUCTION OF 6-CHLORO-1,2ALPHA-METHYLENE DELTA HIGH 4,6-PREGNADIENES |
| DE19681668685 Expired DE1668685C3 (en) | 1967-03-31 | 1968-01-11 | 17-Hydroxy- and 17-acyloxy-6 beta, 7 beta-epoxy-1 alpha, 2 alpha-methylene-4-pregnen-3,20-diones, processes for their preparation and agents containing them |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1967SC040469 Granted DE1643017B2 (en) | 1967-03-23 | 1967-03-31 | PROCESS FOR THE PRODUCTION OF 6-CHLORO-1,2ALPHA-METHYLENE DELTA HIGH 4,6-PREGNADIENES |
Country Status (10)
| Country | Link |
|---|---|
| AT (2) | AT279818B (en) |
| BE (1) | BE712938A (en) |
| CH (2) | CH564039A5 (en) |
| DE (2) | DE1643017B2 (en) |
| DK (2) | DK116941B (en) |
| FR (2) | FR1579547A (en) |
| GB (1) | GB1229428A (en) |
| NL (2) | NL156706B (en) |
| NO (1) | NO127535B (en) |
| SE (2) | SE343056B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH545777A (en) * | 1971-02-05 | 1974-02-15 |
-
1967
- 1967-03-31 DE DE1967SC040469 patent/DE1643017B2/en active Granted
-
1968
- 1968-01-11 DE DE19681668685 patent/DE1668685C3/en not_active Expired
- 1968-02-26 DK DK75068A patent/DK116941B/en not_active IP Right Cessation
- 1968-03-06 AT AT220568A patent/AT279818B/en not_active IP Right Cessation
- 1968-03-12 AT AT244668A patent/AT301038B/en not_active IP Right Cessation
- 1968-03-22 DK DK126368A patent/DK116208B/en unknown
- 1968-03-26 CH CH450768A patent/CH564039A5/xx not_active IP Right Cessation
- 1968-03-27 CH CH451568A patent/CH548382A/en not_active IP Right Cessation
- 1968-03-28 NL NL6804394A patent/NL156706B/en not_active IP Right Cessation
- 1968-03-28 NL NL686804395A patent/NL155020B/en unknown
- 1968-03-29 SE SE422068A patent/SE343056B/xx unknown
- 1968-03-29 SE SE422168A patent/SE331839B/xx unknown
- 1968-03-29 FR FR1579547D patent/FR1579547A/fr not_active Expired
- 1968-03-29 BE BE712938D patent/BE712938A/xx unknown
- 1968-04-01 GB GB1229428D patent/GB1229428A/en not_active Expired
- 1968-06-27 FR FR156884A patent/FR7900M/fr not_active Expired
-
1969
- 1969-01-10 NO NO101/69A patent/NO127535B/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE712938A (en) | 1968-09-30 |
| DE1668685C3 (en) | 1975-04-24 |
| FR1579547A (en) | 1969-08-29 |
| DE1668685A1 (en) | 1971-10-07 |
| DE1643017B2 (en) | 1976-09-09 |
| AT301038B (en) | 1972-08-25 |
| DK116208B (en) | 1969-12-22 |
| SE331839B (en) | 1971-01-18 |
| GB1229428A (en) | 1971-04-21 |
| NL6804395A (en) | 1968-10-01 |
| FR7900M (en) | 1970-05-11 |
| DE1643017A1 (en) | 1971-04-15 |
| CH548382A (en) | 1974-04-30 |
| SE343056B (en) | 1972-02-28 |
| NL156706B (en) | 1978-05-16 |
| NL155020B (en) | 1977-11-15 |
| CH564039A5 (en) | 1975-07-15 |
| DK116941B (en) | 1970-03-02 |
| NL6804394A (en) | 1968-10-01 |
| AT279818B (en) | 1970-03-25 |
| NO127535B (en) | 1973-07-09 |
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| C3 | Grant after two publication steps (3rd publication) | ||
| E77 | Valid patent as to the heymanns-index 1977 |